# Role of myocyte Na+ dysregulation in diabetic heart disease

> **NIH NIH R01** · UNIVERSITY OF KENTUCKY · 2020 · $410,119

## Abstract

ABSTRACT
Type-2 diabetes (T2D) heightens the risk of heart failure, arrhythmias and sudden cardiac death, even in the
absence of vascular complications. However, the underlying mechanisms are poorly understood. We propose
that a critical contributor to diabetic heart disease involves myocyte Na+ dysregulation. Maintenance of cardiac
Na+ homeostasis is vital for preserving heart function. Elevated myocyte Na+ concentration ([Na+]i) causes
oxidative stress and augments the sarcoplasmic reticulum (SR) Ca2+ leak, thus amplifying the risk for
arrhythmias and promoting heart dysfunction. Using a rat model of late-onset T2D (the HIP rat) that displays
myocardial dysfunction and arrhythmias, we recently found that [Na+]i is increased in T2D hearts.
Unexpectedly, higher [Na+]i seems to be caused by enhanced Na+ entry through the Na+-glucose cotransporter
isoform 1 (SGLT1), a previously ignored player in cellular Na+ homeostasis. Furthermore, we found higher
SGLT1 expression in hearts from patients with T2D compared to lean, non-diabetic individuals and in hearts
from diabetic HIP rats vs. control rats. Cardiac-specific SGLT1 overexpression was recently shown to cause
hypertrophy and left-ventricular dysfunction, while SGLT1 activation has been linked to the cardiomyopathy
caused by mutations in the gene encoding the γ2 subunit of AMP-activated protein kinase. Thus, the evidence
that enhanced SGLT1 activity damages the heart is mounting, but little is known about the underlying
mechanisms and its role in diabetic cardiomyopathy. Based on these findings, we hypothesize that SGLT1
upregulation contributes to the multifactorial mechanism driving cardiac remodeling in T2D by perturbing
myocyte Na+ dyshomeostasis. To test this overall hypothesis, we will i) assess the role of SGLT1 activation in
the myocyte [Na+]i rise and consequent oxidative stress, larger SR Ca2+ leak and spontaneous
afterdepolarizations in T2D, ii) test whether SGLT1 upregulation is a maladaptation of the myocardium to
impaired insulin-dependent glucose uptake, and iii) assess whether SGLT1 and [Na+]i are elevated in hearts
from humans with T2D. Experiments will combine fluorescence imaging, electrophysiology, biochemistry, in
vivo assessment of heart function, pharmacological tools, T2D and transgenic animal models and human
studies. By integrating physiological and pharmacological analyses in rat and human hearts, this project will
establish whether SGLT1 activation and Na+ overload are key events in the pathology of diabetic heart disease
and will identify SGLT1 as a new therapeutic target for cardiac complications in T2D patients.

## Key facts

- **NIH application ID:** 9983150
- **Project number:** 5R01HL135000-04
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** Sanda Despa
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $410,119
- **Award type:** 5
- **Project period:** 2017-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9983150

## Citation

> US National Institutes of Health, RePORTER application 9983150, Role of myocyte Na+ dysregulation in diabetic heart disease (5R01HL135000-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9983150. Licensed CC0.

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